Neurodegeneration refers to the progressive death of neurons in the brain, leading to a loss of structure and function. The three most significant disorders that develop following neurodegeneration are Alzheimer’s, Parkinson’s, and Huntington’s disease.
Each disorder displays distinctive symptoms in the early stages of these diseases. A decline in cognitive functioning is characteristic of Alzheimer’s, diminished motor control is often linked with the early stages of Parkinson’s disease, while behavioral changes can be a symptom signifying Huntington’s disease.
Aging - An Important Factor
As we grow older, we become increasingly susceptible to these conditions, and this is thought to be linked to the heightened vulnerability of specific neuronal populations within defined areas of the brain.
It should be noted that around one-tenth of neurons die as a result of ‘healthy’, non-pathological aging. In fact, the protein aggregates which are considered synonymous with Alzheimer’s disease have also been detected in asymptomatic patients.
As a population gets older, the incidence rate of neurodegeneration is likely to show growth. Unfortunately, effective treatments to stop the progression of neurodegenerative disorders are conspicuously lacking, with no robust candidates currently insight.
Alzheimer’s disease is the most commonly diagnosed neurodegenerative disease globally. In 2010, it was estimated that 35.6 million people were affected, with these figures projected to almost double every two decades*, in line with an aging population.
Cause of Neuronal Cell Death In Neurodegenerative
At present, the processes that cause neuronal cell death in neurodegenerative diseases are poorly understood. However, it is thought that neurodegenerative diseases share common cellular and molecular mechanisms.
Each of the three diseases mentioned above is characterized by dysregulation of protein synthesis, degradation, and transport, alongside hallmark features, such as protein misfolding, accumulation into aggregates, and inclusion body formation.
A newly identified mechanism, which is relevant to all neurodegenerative diseases, indicates that cell death may come about through a build-up of misfolded proteins in the brain that over-stimulate a natural defensive mechanism – the unfolded protein response – halting the production of new proteins.
This causes the neuron to become starved of the proteins it requires for regular function and initiates cell death. In current studies, researchers are tackling this mechanism by attempting to inhibit the ‘off’ switch, potentially offering a turning point for the treatment of all neurodegenerative diseases.
Neurons’ Protective Machinery
Neurons have machinery that protects against the accumulation of misfolded and aggregated proteins. If chaperone proteins are unsuccessful in bringing about proper folding, abnormal proteins can be targeted for degradation by attachment of polyubiquitin and targeting to the proteasome for degradation.
Likewise, it is known that the autophagy/lysosomal pathways arbitrate between neuronal survival and death. However, when these processes are compromised, they can play pivotal roles in the pathogenesis of neurodegenerative diseases.
Genetic Components of Neurodegenerative Diseases
Many neurodegenerative diseases have an apparent genetic component. Huntington’s disease is a well-characterized polyglutamine disorder, in which a recurrence of the CAG sequence – which encodes the amino acid glutamine – produces a polyglutamine tract.
These additional glutamine residues prompt irregular protein folding and change protein function, which is lethal to the cell. Alzheimer’s and Parkinson’s disease also have genetic components, with genetic analysis recognizing various genes linked with each disorder, including ApoE4, PINK1, and LRRK2.
A significant example of the genetic component of Alzheimer’s can clearly be seen in people with Down Syndrome who possess the third copy of chromosome 21. Chromosome 21 is also the home of the gene that is linked with the production of the toxic amyloid β plaques in Alzheimer’s disease.
Almost every person with Down Syndrome who has this extra gene copy displays Alzheimer’s disease by 40 years of age.
Another major characteristic that lies beneath neurodegenerative diseases is oxidative stress. Evidence of reactive oxygen species that are deadly to cells has been identified in affected brain regions of Alzheimer’s and Parkinson’s disease patients.
Oxidative stress not only causes harm to cells but can also induce programmed cell death, leading to neurodegeneration. However, it is not known whether the prevalent neuronal cell death witnessed in neurodegenerative diseases is a result of oxidative stress, or is coincident with it. As such, approaches to therapeutically impede oxidative stress may help decrease cell death.
Although neurodegenerative diseases display similarities in the cellular events that take place during the course of the disease, there are fundamental differences between each disorder that demand individual therapeutic approaches.
An example of where this is apparent is in the effects of L-DOPA. This drug eases motor symptoms in Parkinson’s disease, yet in Huntington’s disease, it aggravates motor dysfunction, even though the two diseases share a common cause of protein misfolding.
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